scholarly journals α1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-β

2002 ◽  
Vol 368 (2) ◽  
pp. 581-587 ◽  
Author(s):  
M. Teresa ROMERO-ÁVILA ◽  
C. Fabián FLORES-JASSO ◽  
J. Adolfo GARCÍA-SÁINZ
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Phosphorylation ◽  
Kinase C ◽  
Phosphoinositide 3 Kinase

Transforming growth factor-β (TGF-β) induced α1B-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-β was rapid, reaching a maximum within 30min and decreasing thereafter, and concentration-dependent (EC50 0.3pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. α1B-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [3H]inositol phosphates. Phosphorylation of α1B-adrenergic receptors by TGF-β was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Δp85) inhibited the phosphorylation of α1B-adrenergic receptors induced by TGF-β. Our results indicate that activation of TGF-β receptors induces α1B-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-β.

scholarly journals Phosphorylation of Fli1 at Threonine 312 by Protein Kinase C δ Promotes Its Interaction with p300/CREB-Binding Protein-Associated Factor and Subsequent Acetylation in Response to Transforming Growth Factor β

2009 ◽  
Vol 29 (7) ◽  
pp. 1882-1894 ◽  
Author(s):  
Yoshihide Asano ◽  
Maria Trojanowska
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Creb Binding Protein ◽  
Associated Factor ◽  
Kinase C ◽  
Collagen Promoter

ABSTRACT Previous studies have shown that transforming growth factor β (TGF-β)-induced collagen gene expression involves acetylation-dependent dissociation from the human α2(I) collagen (COL1A2) promoter of the transcriptional repressor Fli1. The goal of this study was to elucidate the regulatory steps preceding the acetylation of Fli1. We first showed that TGF-β induces Fli1 phosphorylation on a threonine residue(s). The major phosphorylation site was localized to threonine 312 located in the DNA binding domain of Fli1. Using several independent approaches, we demonstrated that Fli1 is directly phosphorylated by protein kinase C δ (PKC δ). Additional experiments showed that in response to TGF-β, PKC δ is recruited to the collagen promoter to phosphorylate Fli1 and that this step is a prerequisite for the subsequent interaction of Fli1 with p300/CREB-binding protein-associated factor (PCAF) and an acetylation event. The phosphorylation of endogenous Fli1 preceded its acetylation in response to TGF-β stimulation, and the blockade of PKC δ abrogated both the phosphorylation and acetylation of Fli1 in dermal fibroblasts. Promoter studies showed that a phosphorylation-deficient mutant of Fli1 exhibited an increased inhibitory effect on the COL1A2 gene, which could not be reversed by the forced expression of PCAF or PKC δ. These data strongly suggest that the phosphorylation-acetylation cascade triggered by PKC δ represents the primary mechanism whereby TGF-β regulates the transcriptional activity of Fli1 in the context of the collagen promoter.

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